The objective of the current proposal is to develop methods and directly assess receptor sensitivity in patients receiving long-term antidepressant drug treatment. Antidepressant drugs differ on many biochemical and physiologic parameters, but in rats changes in adrenergic and serotonergic receptor sensitivity following long-term treatment have been found with most compounds. However, there is no direct clinical confirmation that these changes are occurring in patients. Initial studies in rhesus monkeys will evaluate tests involving determination of the relative sensitivity of plasma MHPG, growth hormone and prolactin to adrenergic and serotonergic agonist and antagonist drugs and determination of proper routes of administration and dose response curves. Once that sensitive challenge tests are developed, the effect of acute and chronic administration of 3 clinically effective but structurally and biochemically dissimilar antidepressant drugs will be studied in rhesus monkeys. Those tests found to be altered with either acute or chronic drug treatments will then be given to control subjects. Depressed patients will be studied with these tests before and after chronic treatment with the same three drugs studied in rhesus monkeys. In patients, the changes in the measures of receptor sensitivity will be evaluated relative to direct drug effects, clinical improvement, and the interaction of these two dimensions. This study is designed to provide direct clinical evidence evaluating the hypothesis that a common mechanism of biochemically different but equally clinically effective antidepressant drug treatments is to increase the sensitivity of adrenergic and serotonergic receptors. The information obtained from this study will be important for the development of more efficacious antidepressant drug treatments. In addition, we plant to study the acute antidepressant effects of lithium carbonate treatment in depressed patients not responding to long-term antidepressant drug treatment and to assess the relationship of serotonin metabolism to antidepressant drug effects by studying the effects of high and low tryptophan intake on the efficacy of the antidepressant drug treatment.